Medical use for tachykinin antagonists

ABSTRACT

The present invention relates to the use of tachykinin antagonists, including substance P antagonists and other neurokinin antagonists, in the treatment of emesis. Also described are novel tachykinin antagonists of formula (I), processes for their preparation, pharmaceutical compositions containing them and their medical use. ##STR1## wherein R represents the ring A ##STR2##  or 2-pyridinyl or 2-pyridinyl-N-oxide; R 1  is selected from halogen atoms and C 1-4  alkyl, C 1-4  alkoxy, trifluoromethyl, and S(O) n  C 1-4  alkyl groups; 
     R 2  and R 3 , which may be the same or different, each independently are selected from hydrogen and halogen atoms and C 1-4  alkyl, C 1-4  alkoxy, trifluoromethyl and cyano groups; 
     n represents zero, 1 or 2; 
      and pharmaceutically acceptable salts and solvates thereof.

This application is a Division of application Ser. No. 07/946,635, filedSep. 18, 1992, issued as U.S. Pat. No. 5,360,820.

The present invention relates to the use of tachykinin antagonists,including substance P antagonists and other neurokinin antagonists, inthe treatment of emesis. Also described are novel tachykininantagonists, processes for their preparation, pharmaceuticalcompositions containing them and their medical use.

Tachykinin antagonists are known to be useful in the treatment of avariety of disorders including pain, inflammatory diseases, allergicdisorders, CNS disorders, skin disorders, cough and gastrointestinaldisorders such as ulcerative colitis and Crohn's disease.

It has now been found that tachykinin antagonists, including substance Pantagonists and other neurokinin antagonists, are useful in thetreatment of emesis.

The invention accordingly provides, in a first aspect, the novel use oftachykinin antagonists, including substance P antagonists and otherneurokinin antagonists, in the treatment of emesis.

There is also provided as a further aspect of the invention the use oftachykinin antagonists, including substance P antagonists and otherneurokinin antagonists, in the preparation of a medicament for use inthe treatment of emesis.

In an alternative or further aspect there is provided a method for thetreatment of a mammal, including man, suffering from or susceptible toemesis, comprising administration of an effective amount of a tachykininantagonist, including substance P antagonists and other neurokininantagonists.

It will be appreciated that reference to treatment is intended toinclude prophylaxis as well as the alleviation of established symptoms.

Tachykinin antagonists, including substance P antagonists and otherneurokinin antagonists, have been shown to have anti-emetic activity asindicated by for example their ability to inhibit cisplatin-inducedemesis in the ferret.

The treatment of emesis mentioned hereinbefore includes the treatment ofnausea, retching and vomiting. Emesis includes acute emesis, delayedemesis and anticipatory emesis. Tachykinin antagonists, includingsubstance P antagonists and other neurokinin antagonists, are useful inthe treatment of emesis however induced. For example, emesis may beinduced by drugs such as cancer chemotherapeutic agents such asalkylating agents, e.g. cyclophosphamide, carmustine, lomustine andchlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin,mitomycin-C and bleomycin; anti-metabolites, e.g. cytarabine,methotrexate and 5-fluorouracil; vinca alkaloids, e.g. etoposide,vinblastine and vincristine; and others such as cisplatin, dacarbazine,procarbazine and hydroxyurea; and combinations thereof; radiationsickness; radiation therapy, e.g. irradiation of the thorax or abdomen,such as in the treatment of cancer; poisons; toxins such as toxinscaused by metabolic disorders or by infection, e.g. gastritis;pregnancy; vestibular disorders, such as motion sickness; post-operativesickness; gastrointestinal obstruction; reduced gastrointestinalmotility; visceral pain, e.g. myocardial infarction or peritonitis;migraine; increased intercranial pressure; decreased intercranialpressure (e.g. altitude sickness); and opioid analgesics, such asmorphine.

Tachykinin antagonists acting at NK₁ receptors have been found to beparticularly useful in the treatment of emesis.

In a preferred aspect therefore the invention provides the use of an NK₁receptor antagonist in the treatment of emesis.

Specific tachykinin antagonists for use in the present invention includethose generically and specifically disclosed in the following patentspecifications which disclosures are incorporated herein by reference:

EP 0327009;

WO 91/12266;

EP 0284942;

GB 2216529;

U.S. Pat. No. 4,839,465;

WO 91/02745

EP 0484719;

WO 91/18016;

EP 0482539;

EP 0446706

Particularly preferred are the tachykinin antagonists disclosed in:

EP 0360390 in particular:

N-[N¹-[L-pyroglutamyl-L-alanyl-L-aspartyl-L-prolyl-L-asparaginyl-L-lysyl-L-phenylalanyl-L-tyrosyl]-4-methyl-1-oxo-2S-(6-oxo-5S-1,7-diazaspiro[4.4]non-7-yl)pentyl]-L-tryptophanamideand

N-[N¹-[L-arginyl-L-prolyl-L-lysyl-L-prolyl-L-glutaminyl-L-glutaminyl-L-phenylalanyl-L-phenylalanyl]-4-methyl-1-oxo-2S-(6-oxo-5S-1,7-diazaspiro[4.4]nonan-7-yl)-pentyl]-L-tryptophanamide;

WO 90/05525

WO 90/05729 i.e. quinuclidine derivatives of the formulae: ##STR3##including the pharmaceutically acceptable salts thereof; wherein Ar isthienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl; R ishydrogen or alkyl having from one to four carbon atoms; R¹ is cycloalkylhaving from five to seven carbon atoms, norbornyl, pyrrolyl,2,3-dihydrobenzofuranyl, thienyl, alkoxythienyl having from one to threecarbon atoms in the alkoxy moiety, pyridyl, hydroxypyridyl, quinolinyl,indolyl, naphthyl, alkoxynaphthyl having from one to three carbon atomsin the alkoxy moiety, biphenyl 2,3-methylenedioxyphenyl, or phenyloptionally substituted with up to two substituents selected from cyano,nitro, amino, N-monoalkylamino having from one to three carbon atoms inthe alkyl moiety, fluorine, chlorine, bromine, trifluoromethyl, alkylhaving from one to three carbons, alkoxy having from one to three carbonatoms, allyloxy, hydroxy, carboxy, alkoxycarbonylbenzyloxy having fromone to three carbon atoms in the alkoxy moiety, carboxamido orN,N-dialkylcarboxamido having from one to three carbon atoms in thealkyl moiety; and R¹¹ is branched chain alkyl having from three to fourcarbon atoms, branched chain alkenyl having from five to six carbonatoms, cycloalkyl having from five to seven carbon atoms, furyl,thienyl, pyridyl, indolyl, biphenyl, or phenyl optionlly substitutedwith up to two substituents selected from fluorine, chlorine, bromine,trifluoromethyl, alkyl having from one to three carbon atoms, alkoxyhaving from one to three carbon atoms, carboxy, alkoxycarbonyl havingfrom one to three carbon atoms in the alkoxy moiety orbenzyloxycarbonyl, with the proviso that said R¹¹ is always other thanunsubstituted phenyl, fluorophenyl, chlorophenyl, bromophenyl oralkylphenyl when said R¹ is unsubstituted phenyl, pyrrolyl or thienyland Ar is other than thienyl;

for examplecis-3-[(2-methoxyphenyl)methylamino]-2-benzhydryl-quinuclidine;

WO 91/18899 i.e. compounds of the formula: ##STR4## wherein R¹ ishydrogen or (C₁ -C₆)alkyl; R² is phenyl, pyridyl, thienyl or furyl, andR² may optionally be substituted with from one to three substituentsindependently selected from (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, chloro,fluoro, bromo, iodo and trifluoromethyl; R³ is phenyl, naphthyl,pyridyl, thienyl or furyl, and R³ may optionally be substituted with oneto three substituents independently selected from (C₁ -C₄)alkyl, (C₁-C₄)alkoxy, chloro, fluoro, bromo, iodo and trifluoromethyl; and thepharmaceutically acceptable salts of such compounds;

WO 92/01688 i.e. compounds of the formula: ##STR5## wherein Y is(CH₂)_(m) wherein m is an integer from one to three, or Y is a group ofthe formula ##STR6## P is an integer from zero to one; Z is oxygen,sulfur, amino, N--(C₁ -C₃) alkylamino or --(CH₂)_(n) -- and n is zero,one or two;

Ar is thienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl; R¹ iscycloalkyl having from five to seven carbon atoms, pyrrolyl, thienyl,pyridyl, phenyl or substituted phenyl, wherein said substituted phenylis substituted with one to three substituents selected from fluorine,chlorine, bromine, trifluoromethyl, alkyl having from one to threecarbon atoms, alkoxy having from one to three carbon atoms, carboxy,alkoxycarbonyl having from one to three carbons in the alkoxy moiety andbenzyloxycarbonyl; and

R² is furyl, thienyl, pyridyl, indolyl, biphenyl, phenyl or substitutedphenyl, wherein said substituted phenyl is substituted with one or twosubstituents selected from fluroine, chlorine, bromine, trifluoromethyl,alkyl having from one to three carbon atoms, alkoxy having from one tothree carbon atoms, carboxy, alkoxycarbonyl having from one to threecarbon atoms in the alkoxy moiety and benzyloxycarbonyl,

or a pharmaceutically acceptable salt thereof; for example

8-benzhydryl-n-phenylmethyl]-9-azatricyclo[4.3.-1.0⁴.9 ]decan-7-amine;

8-benzhydryl-n-[(2-chlorophenyl)methyl]-9-azatricyclo[4.3.-1.0⁴.9]decan-7-amine;

8-benzhydryl-n-[(4-trifluoromethylphenyl)methyl]-9-azatricyclo[4.3.-1.0.sup.4.9]decan-7-amine; or

8-benzhydryl-n-[(2-methoxyphenyl)methyl]-9-azatricyclo[4.3.-1.0⁴.9]decan-7-amine.

WO 92/06079 i.e. compounds of the formula: ##STR7## wherein X is aninteger from zero to four; Y is an integer from zero to four;

z is an integer from one to six;

the ring containing (CH₂)_(z) may contain from zero to three doublebonds, and one of the carbons of (CH₂)_(z) may optionally be replaced byoxygen, sulfur or nitrogen;

m is an integer from zero to twelve, and any one of the carbon-carbonsingle bonds of (CH₂)_(m) may optionally be replaced by a carbon-carbondouble or triple bond and any one of the carbon atoms of said (CH₂)_(m)may optionally be substituted with R⁸ ;

R¹ is hydrogen or (C₁ -C₆)alkyl optionally substituted with hydroxy,alkoxy or fluoro;

R² is a radical selected from hydrogen, (C₁ -C₆) straight or branchedalkyl, (C₃ -C₇) cycloalkyl wherein one of the carbon atoms mayoptionally be replaced by nitrogen, oxygen or sulfur; aryl selected fromphenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl,pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl,tetrazolyl and quinolyl; phenyl (C₂ -C₆)alkyl, benzhydryl and benzyl,wherein each of said aryl and heteroaryl groups and the phenyl moietiesof said benzyl, phenyl (C₂ -C₆) alkyl and benzhydryl groups mayoptionally be substituted with one or more substituents independentlyselected from halo, nitro, (C₁ -C₆)alkyl, (C₁ -C₆) alkoxy,trifluoromethyl, amino, (C₁ -C₆)-alkylamino, (C₁ -C₆)alkyl-O-C(O), (C₁-C₆)alkyl-O-C(O)(C₁ -C₆)alkyl,(C₁ -C₆)alkyl-CO₂ -, (C₁-C₆)alkyl-C(O)-(C₁ -C₆)alkyl-O-, (C₁ -C₆)alkyl-C(O)-, (C₁-C₆)alkyl-C(O)-(C₁ -C₆)alkyl-, di-(C₁ -C₆)alkylamino, --CONH-(C₁-C₆)alkyl, (C₁ -C₆)alkyl-CONH-(C₁ -C₆)alkyl, --NHC(O)H and --NHC(O)(C₁-C₆)alkyl;

R⁵ is hydrogen or (C₁ -C₆)alkyl;

or R² and R⁵, together with the carbon to which they are attached, forma saturated carbocyclic ring having from 3 to 7 carbon atoms, whereinone of said carbon atoms may optionally be replaced by oxygen, nitrogenor sulfur;

R³ is aryl selected from phenyl and naphthyl; heteroaryl selected fromindanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, triazolyl, tetrazolyl and quinolyl; or cycloalkyl havingfrom three to seven carbon atoms, wherein one of said carbon atoms mayoptionally be replaced by nitrogen, oxygen or sulfur; wherein each ofsaid aryl and heteroaryl groups may optionally be substituted with oneor more substitutents and said (C₃ -C₇) cycloalkyl may optionally besubstituted with one or two substituents, said substituents beingindependently selected from halo, nitro, (C₁ -C₆) alkyl, (C₁ -C₆)alkoxy, trifluoromethyl, amino, phenyl, (C₁ -C₆)alkylamino, --CONH-(C₁-C₆)alkyl, (C₁ -C₆)alkyl-CONH-(C₁ -C₆)alkyl, --NHC(O)H and --NHC(O)-(C₁-C₆) alkyl;

R⁴ may be attached to any atom of the nitrogen containing ring having anavailable bonding site and R⁷ may be attached to any atom of the(CH₂)_(z) containing ring having an available bonding site;

R⁴, R⁶, R⁷ and R⁸ are each independently selected from hydrogen,hydroxy, halo, amino, carboxy, carboxyalkyl, (C₁ -C₆)alkylamino, di-(C₁-C₆)alkylamino, (C₁ -C₆)alkoxy, (C₁ -C₆)alkyl-O-C(O)--, (C₁-C₆)alkyl-O-C(O)-(C₁ -C₆)alkyl, (C₁ -C₆)alkyl-CO₂, (C₁-C₆)alkyl-C(O)-(C₁ -C₆)alkyl-O-(C₁ -C₆)alkyl-C(O)--, (C₁-C₆)alkyl-C(O)(C₁ -C₆)alkyl, and the radicals set forth in thedefinition of R², with the proviso that (a) when m is O, R⁸ is absent,(b) neither R⁴, R⁶, R⁷ nor R⁸ can form, together with the carbon towhich it is attached, a ring with R⁵, and (c) R⁴ and R⁷ can not beattached the same carbon atom;

or a pharmaceutically acceptable salt thereof; for example [1α, 3α, 4α,5α]-4-(2-methoxybenzyl)amino-3-phenyl-2-azabicyclo[3.3.0]octane;4-(2-methoxybenzyl)amino-3-phenyl-2-azabicyclo[4.4.0]decane; or4-(2-methoxybenzyl)amino-4-benzhydryl-3-azabicyclo[4.1.0]heptane.

EP 0429366 i.e. isoindoline derivatives of the formula: ##STR8## in the(3aR, 7aR) and (3aRS, 7aRS) forms, and mixtures and salts thereof where

R represents hydrogen, or together R and R form a bond;

R' are identical and represent phenyl, optionally substituted by halogenor methyl in position 2 or 3;

X represents O, S or NR₃ ;

R₃ represents hydrogen, C₁ -₁₂ alkyl (optionally substituted by one ormore carboxy, dialkylamino, acylamino, alkoxycarbonyl,alkoxycarbonylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl (wherethe alkyl portions of these radicals may contain a dialkylamino orphenyl substituent), phenyl (optionally substituted by halogen, alkyl,alkoxy or dialkylamino), naphthyl, thienyl, furyl, pyridyl orimidazolyl); or dialkylamino;

R₁ represents phenyl (optionally substituted by 1 or more halogen, OH,alkyl (optionally substituted by halogen, amino, alkylamino ordialkylamino), alkoxy or alkylthio (optionally substituted by OH ordialkylamino of which the alkyl portions may form a 5- to 6-memberedheterocycle which can contain another O, S or N heteroatom), orsubstituted by amino, alkylamino or dialkylamino); or R₁ is acyclohexadienyl, naphthyl or (un)saturated 5-9C mono or polycyclicheterocyclyl having one or more O, N or S heteroatoms;

R₂ represents H, halogen, OH, alkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, alkoxy, alkylthio, acyloxy, carboxy, alkoxycarbonyl,dialkylaminoalkoxycarbonyl, benxyloxycarbonyl, amino, acylamino oralkoxycarbonylamino; the various alkyl and acyl groups being straight orbranched and of 1-4C atoms; for example ##STR9##

EP 04284434 i.e. 1,4-diaralkylpiperidine and piperazine derivatives ofthe formula: ##STR10## where m=1-3;

Ar, Ar¹ represents thienyl; phenyl optionally mono- or disubstituted byhalogen, 1-3C alkyl, CF₃, 1-3 C alkoxy, OH or methylenedioxy; orimidazolyl; or Ar¹ may also be benzothienyl optionally substituted byhalogen; naphthyl optionally substituted by halogen; biphenylyl; orindolyl optionally substituted by benzyl;

X¹ represents hydrogen or OH;

Y represents N or CX¹¹ ;

X and X¹¹ represent hydrogen; or X¹ or X¹¹ is a bond; or X and X¹represent O or NO(CH₂)pAm;

p represents 2 or 3;

Am represents di(1-4Calkyl)amino;

Q represents hydrogen, 1-4Calkyl or (CH₂)qAm;

q represents 2 or 3;

Am represents piperidino, 4-benzylpiperidino or di(1-4Calkyl)amino;

R represents hydrogen, methyl or (CH₂)_(n) L;

L represents hydrogen or NH₂ ;

n represents 2-6;

T represents COM, COOM, CONHM or CSNHM;

M represents hydrogen, 1-6C alkyl, phenyl(1-3C)alkyl (optionallyring-substituted by halogen, OH, 1-4C alkoxy or 1-4C alkyl),pyridyl(1-3C)alkyl, naphthyl(1-3C)alkyl, pyridylthio(1-3C)alkyl, styryl,1-methyl-2-imidazolylthio(1-3C) alkyl, 1-oxo-3-phenyl-2-indanyl oroptionally substituted aryl or heteroaryl; and optical isomers and acidaddition salts thereof;

EP 0336230 i.e. compounds of the formula: ##STR11## wherein R¹ ishydrogen or an acyl group;

R² is hydroxy and

R³ is carboxy or protected carboxy, or

R² and R³ are linked together to represent a group of the formula:--O--C(O);

R⁴ is hydroxy or protected hydroxy;

R⁵ is hydroxy or protected hydroxy;

R⁶ is hydroxy, protected hydroxy or lower alkoxy; and

is a single bond or a double bond;

for example ##STR12##

EP 0333174 i.e. compounds of the formula

    R.sup.1 -A-D-Trp(R.sup.2)-Phe-R.sup.3                      P

wherein

R¹ is hydrogen or an amino protective group;

R² is hydrogen, an amino protective group, carbamoyl(lower) alkyl,carboxy (lower) alkyl or protected carboxy(lower) alkyl;

R³ is ar(lower)aklyl;

a group of the formula ##STR13## wherein R⁴ and R⁵ are each hydrogen,aryl or lower alkyl which may have suitable substituent(s) or

R⁴ and R⁵ are linked together to form benzene-condensed lower alkylene,or a group of the formula: --OR⁶

wherein R⁶ is hydrogen, aryl or lower alkyl which may have suitablesubstituent(s), and A is a single bond or one or two amino acid(s)residue, provided that when A is one amino acid residue of -D-Trp-, thenR⁴ is not hydrogen;

and a pharmaceutically acceptable salt thereof

for example ##STR14##

EP 0394989 i.e. compounds of the formula ##STR15##

wherein R¹ is lower alkyl, aryl, arylamino, pyridyl, pyrrolyl,pyrazolopyridyl, quinolyl, or a group of the formula: ##STR16## whereinthe symbol of a line and dotted line is a single bond or double bond,

X is CH or N, and

Z is O, S or NH,

each of which may have suitable substituents(s);

R² is hydrogen or lower alkyl;

R³ is hydrogen or hydroxy;

R⁴ is lower alkyl which may have suitable substituent(s), and

R⁵ is ar(lower)alkyl which may have suitable substituent(s) orpyridyl(lower)alkyl, or

R⁴ and R⁵ are linked together to form benzene-condensed lower alkylene;

A is an amino acid residue excepting D-Trp, which may have suitablesubstituent(s); and

Y is a bond, lower alkylene or lower alkenylene;

for example ##STR17##

EP 0443132 i.e. compounds of the formula: ##STR18## wherein R¹ is aryl,or a group of the formula: ##STR19## wherein X is CH or N, and

Z is O or N--R⁵, in which R⁵ is hydrogen or lower alkyl,

R² is hydroxy or lower alkoxy,

R³ is hydrogen lower alkyl which may have suitable substituent(s),

R⁴ is ar(lower)alkyl which may have suitable substituent(s),

A is carbonyl or sulfonyl, and

Y is bond, or lower alkenylene;

for example ##STR20##

EPO499313 i.e. compounds of the formula ##STR21## wherein Q is theresidue of an optionally substituted azabicyclic ring system;

X represents oxa or thia;

Y represents H or hydroxy;

R¹ and R² independently represent phenyl or thienyl, either of whichgroups may be optionally substituted by halo or trifluoromethyl;

R³, R⁴ and R⁵ independently represent H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, --OR^(a),SCH₃, SOCH₃, SO₂ CH₃, --NR^(a) R^(b), NR^(a) COR^(b), NR^(a) CO₂ R^(b),--CO₂ R^(a) or --CONR^(a) R^(b) ; and

R^(a) and R^(b) independently represent H, C₁₋₆ alkyl, phenyl ortrifluoromethyl; or a salt or prodrug thereof;

for examplecis-(2S,3S)-3-[3,5-bis(trifluoromethyl)benzyloxy]-2-(diphenylmethyl)-1-azabicyclo]2.2.2]octane.

EP 0436334 i.e. compounds of the formula: ##STR22## wherein Y is(CH₂)_(n) wherein n is an integer from 1 to 4, and wherein any one ofthe carbon-carbon single bonds in said (CH₂)_(n) may optionally bereplaced by a carbon-carbon double bond, and wherein any one of thecarbon atoms of said (CH₂)_(n) may optionally be substituted with R⁴ andwherein any one of the carbon atoms of said (CH₂)_(n) may optionally besubstituted with R₇ ;

Z is (CH₂)_(m) wherein m is an integer from 0 to 6, and wherein any oneof the carbon-carbon single bonds of (CH₂)_(m) may optionally bereplaced by a carbon-carbon double bond or carbon-carbon triple bond,and any one of the carbon atoms of said (CH₂)_(m) may optionally besubstituted with R⁸ ;

R¹ is hydrogen or (C₁ -C₈) alkyl optionally substituted with hydroxy,(C₁ -C₄)alkoxy or fluoro;

R² is a radical selected from hydrogen, (C₁ -C₆) straight or branchedalkyl, (C₃ -C₇) cycloalkyl wherein one of the CH₂ groups in saidcycloalkyl may optionally be replaced by NH, oxygen or sulfur; arylselected from phenyl and naphthyl; heteroaryl selected from indanyl,thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,triazolyl, tetrazolyl and quinolyl; phenyl-(C₂ -C₆)alkyl, benzhydryl andbenzyl, wherein each of said aryl and heteroaryl groups and the phenylmoieties of said benzyl, phenyl(C₂ -C₆)-alkyl and benzhydryl mayoptionally be substituted with one or more substituents independentlyselected from halo, nitro, (C₁ -C₆) alkyl, (C₁ -C₆) alkoxy,trifluoromethyl, amino, (C₁ -C₆)-alkylamino, (C₁ -C₆)alkyl-O-C(O)--, (C₁-C₆)alkyl-O--C(O)--(C₁ -C₆)alkyl, (C₁ -C₆)alkyl-C(O)--O--, (C₁-C₆)alkyl-C(O)--, (C₁ -C₆)alkyl-O--, (C₁ -C₆)alkyl-C(O)--, (C₁-C₆)alkyl-C(O)-(C₁ -C₆)alkyl-, di-(C₁ -C₆)alkylamino,--CONH-(C₁₋₆)alkyl, (C₁ -C₆)-alkyl-CONH-(C₁ -C₆)alkyl, NHC(O)H and--NHC(Q)-(C₁ -C₆) alkyl;

and wherein one of the phenyl moieties of said benzhydryl may optionallybe replaced by naphthyl, thienyl, furyl or pyridyl; R⁵ is hydrogen,phenyl or (C₁ -C₆) alkyl; or R² and R⁵, together with the carbon towhich they are attached, form a saturated ring having from 3 to 7 carbonatoms wherein one of the CH₂ groups in said ring may optionally bereplaced by oxygen, NH or sulfur;

R³ is aryl selected from phenyl and naphthyl; heteoaryl selected fromindanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, triazolyl; tetrazolyl and quinolyl; and cycloalkyl having 3to 7 carbon atoms wherein one of the (CH₂) groups in said cycloalkyl mayoptionally be replaced by NH, oxygen or sulfur;

wherein each of said aryl and heteroaryl groups may optionally besubstituted with one or more substituents, and said (C₃ -C₇) cycloalkylmay optionally be substituted with one or two substituents, each of saidsubstituents being independently selected from halo, nitro, (C₁ -C₆)alkyl, (C₁ -C₆) alkoxy, trifluoromethyl, amino, (C₁ -C₆) alkylamino,--CONH-(C₁ -C₆)alkyl, (C₁ -C₆)alkyl-C(O)-NH-(C₁ -C₆)alkyl, --NHC(O)H and--NHC(O)-(C₁ -C₆)alkyl; and

R⁴ and R⁷ are each independently selected from hydroxy, hydrogen, halo,amino, oxo, cyano, methylene, hydroxymethyl, halomethyl, (C₁-C₆)alkylamino, di-(C₁ -C₆)alkylamino, (C₁ -C₆) alkoxy, (C₁-C₆)alkyl-O--C(O)--, (C₁ -C₆)alkyl-O--C(O)-(C₁ -C₆)alkyl, (C₁-C₆)alkyl-C(O), (C₁ -C₆)alkyl-C--(O)-(C₁ -C₆)alkyl-O, (C₁-C₆)alkyl-C(O), (C₁ -C₆)alkyl-C(O)-(C₁ -C₆)alkyl-, and the radicals setforth in the definition of R², R⁶ is NHC(O)R⁹, --NHCH₂ R⁹, SO₂ R⁹ or oneof the radicals set forth in any of the definitions of R², R⁴ and R⁷ ;

R⁸ is oximino (═NOH) or one of the radicals set forth in any of thedefinitions of R², R⁴ and R⁷ ;

R⁹ is (C₁ -C₆)alkyl, hydrogen, phenyl or phenyl(C₁ -C₆)alkyl;

with the proviso that (a) when m is O, R⁸ is absent, (b) when R⁴, R⁶, R⁷or R⁸ is as defined in R², it cannot form, together with the carbon towhich it is attached, a ring with R⁵, and (C) when R⁴ and R⁷ areattached to the same carbon atom, then either each of R⁴ and R⁷ isindependently selected from hydrogen, fluoro and (C₁ -C₆) alkyl, or R⁴and R⁷, together with the carbon to which they are attached, form a (C₃-C₆) saturated carbocyclic ring that forms a spiro compound with thenitrogen-containing ring to which they are attached; andpharmaceutically acceptable acid addition salts thereof;

in particular cis-3-(2-methoxybenzylamino)-2-phenyl piperidine, moreparticularly the (2S,3S) or (+) enantiomer thereof.

Of the above, the most preferred tachykinin antagonists for use in thepresent invention are found within WO 90/05525, WO90/05729, WO91/18899,WO92/01688, WO92/06079, EPO499313 and, more preferably, EPO436334, i.e.compounds of the formulae A,B,C,D,E,F,G,H,V' and, more preferably, W asdefined hereinbefore.

Also preferred for use in the present invention are the compounds offormula (I) defined hereinafter.

The tachykinin antagonists may be administered as the raw chemical butthe active ingredients are preferably presented as a pharmaceuticalformulation. Suitable pharmaceutical formulations are described in theabove referenced patent specifications.

Thus, the tachykinin antagonists may be formulated for oral, buccal,parenteral, depot or rectal administration or in a form suitable foradministration by inhalation or insufflation (either through the mouthor nose). Oral and parenteral formulations are preferred.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talcor silica); disintegrants (e.g. potato starch or sodium starchglycollate); or wetting agents (e.g. sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters, ethyl alcohol or fractionated vegetable oils);and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbicacid). The preparations may also contain buffer salts, flavouring,colouring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration the composition may take the form of tabletsor lozenges formulated in conventional manner.

The tachykinin antagonists may be formulated for parenteraladministration by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form e.g. in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form for constitution with a suitablevehicle, e.g. sterile pyrogen-free water, before use.

The tachykinin antagonists may be formulated for topical administrationin the form of ointments, creams, gels, lotions, pessaries, aerosols ordrops (e.g. eye, ear or nose drops). Ointments and creams may, forexample, be formulated with an aqueous or oily base with the addition ofsuitable thickening and/or gelling agents. Ointments for administrationto the eye may be manufactured in a sterile manner using sterilisedcomponents.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents, thickening agents, or colouringagents. Drops may be formulated with an aqueous or non aqueous base alsocomprising one or more dispersing agents, stabilising agents,solubilising agents or suspending agents. They may also contain apreservative.

The tachykinin antagonists may also be formulated in rectal compositionssuch as suppositories or retention enemas, e.g. containing conventionalsuppository bases such as cocoa butter or other glycerides.

The tachykinin antagonists may also be formulated as depot preparations.Such long acting formulations may be administered by implantation (forexample subcutaneously or intramuscularly) or by intramuscularinjection. Thus, for example, the compounds of the invention may beformulated with suitable polymeric or hydrophobic materials (for exampleas an emulsion in an acceptable oil) or ion exchange resins, or assparingly soluble derivatives, for example, as a sparingly soluble salt.

For intranasal administration, the tachykinin antagonists may beformulated as solutions for administration via a suitable metered orunit dose device or alternatively as a powder mix with a suitablecarrier for administration using a suitable delivery device.

Suitable dose ranges are also described in the above referenced patentspecifications, that is to say that for use as anti-emetics thecompounds may be used at doses appropriate for other conditions forwhich tachykinin antagonists are known to be useful. It will beappreciated that it may be necessary to make routine variations to thedosage, depending on the age and condition of the patient, and theprecise dosage will be ultimately at the discretion of the attendantphysician or veterinarian. The dosage will also depend on the route ofadministration and the particular compound selected. A suitable doserange is for example 0.1 mg/kg to about 400 mg/kg bodyweight per day.

The tachykinin antagonists may, if desired, be administered incombination with one or more other therapeutic agents and formulated foradministration by any convenient route in a conventional manner.Appropriate doses will be readily appreciated by those skilled in theart. For example, the tachykinin antagonists may be administered incombination with a systemic anti-inflammatory corticosteroid such asmethyl prednisolone or dexamethasone, or a 5HT₃ antagonist such asondansetron, granisetron or metoclopramide.

The present invention also relates to novel compounds which are potentand specific antagonists of tachykinins, including substance P and otherneurokinins.

The art relating to tachykinin antagonists is discussed hereinbefore,see for example WO90/05729 relating to quinuclidine derivatives and EP0436334.

Thus, in a further aspect the present invention provides a2,2,1-azabicycloheptane derivative of formula (I) ##STR23## wherein Rrepresents the ring A ##STR24## or 2-pyridinyl or 2-pyridinyl-N-oxide;R¹ is selected from halogen atoms and C₁₋₄ alkyl, C₁₋₄ alkoxy,trifluoromethyl, and S(O)_(n) C₁₋₄ alkyl groups;

R² and R³, which may be the same or different, each independently areselected from hydrogen and halogen atoms and C₁₋₄ alkyl, C₁₋₄ alkoxy,trifluoromethyl and cyano groups;

n represents zero, 1 or 2;

and pharmaceutically acceptable salts and solvates thereof.

Suitable pharmaceutically acceptable salts of the compounds of generalformula (I) include acid addition salts formed with pharmaceuticallyacceptable organic or inorganic acids for example, hydrochlorides,hydrobromides, sulphates, alkyl- or arylsulphonates (e.g.methanesulphonates or p-toluenesulphonates), phosphates, acetates,citrates, succinates, tartrates, fumarates and maleates.

Other acids, such as oxalic, while not in themselves pharmaceuticallyacceptable, may be useful in the preparation of salts useful asintermediates in obtaining the compounds of formula (I) and theirpharmaceutically acceptable acid addition salts.

The solvates may, for example, be hydrates.

It will be appreciated by those skilled in the art that the compounds offormula (I) contain at least three chiral centres (shown as * in formula(I)) and thus exist in the form of four pairs of optical isomers (i.e.enantiomers) and mixtures thereof including racemic mixtures.

For example the compounds of formula (I) may be either cis isomers, asrepresented by figures (a) and (b), or trans isomers, as represented byfigures (c) and (d), or mixtures thereof.

All of the isomers represented by the figures (a) to (d) can exist asone of two enantiomers or as mixtures thereof including racemicmixtures. All such isomers of the compounds of formula (I) and mixturesthereof including racemic mixtures are included within the scope of theinvention. ##STR25##

The compound of formula (I) are preferably in the form of their cisisomers (i.e. as represented by figures (a) and (b)).

Referring to the general formula (I), a C₁₋₄ alkyl group may be astraight chain or branched chain alkyl group, for example, methyl,ethyl, propyl, prop-2-yl, butyl, but-2-yl or 2-methylprop-2-yl. A C₁₋₄alkoxy group may be a straight chain or branched chain alkoxy group, forexample, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or2-methylprop-2-oxy.

Referring to the general formula (I), a halogen atom may be, forexample, a fluorine, chlorine, bromine or iodine atom.

When R represents the ring A, R² and R³ may be attached at either the3-,4-,5- or 6-(e.g. the 3- and 5-) positions of the phenyl ring.

A preferred class of compounds of formula (I) is that in which Rrepresents the ring A and R¹ represents a C₁₋₄ alkoxy (e.g. methoxy) orS(O)_(n) C₁₋₄ alkyl group, preferably where n is zero or 1 (e.g. SOMe orSMe). Preferably R¹ represents C₁₋₄ alkoxy (e.g. methoxy).

Another preferred class of compounds of formula (I) is that in which Rrepresents the ring A and R² and/or R³ represents a hydrogen or ahalogen (e.g. fluorine) atom, or a cyano group. Preferably R² and/or R³represents a hydrogen or a halogen (e.g. fluorine) atom.

A further preferred class of compounds of formula (I) is that in which Rrepresents the ring A and one of R² and R³ represents hydrogen and theother represents a hydrogen atom or a halogen (e.g. fluorine) atompreferably at the 5-position of the phenyl ring.

Further preferred are compounds of formula (I) where R represents thering A where R¹ represents C₁₋₄ alkoxy (e.g. methoxy) or S(O)_(n) C₁₋₄alkyl, preferably where n is zero or 1 (e.g. SOMe or SMe) and one of R²and R³ represents hydrogen and the other represents a hydrogen orhalogen (e.g. fluorine) atom.

Preferred compounds of formula (I) according to the invention are

(exo,exo)-2-(Diphenylmethyl)-N-[(2-methoxyphenyl)methyl]-1-azabicyclo[2.2.1]heptan-3-amine;

(exo,exo)-2-(Diphenylmethyl)-N-[(5-fluoro-2-methoxyphenyl)methyl]-1-azabicyclo[2.2.1]heptan-3-amine;

(endo,endo)-2-(Diphenylmethyl)-N-[(2-methoxyphenyl)methyl]-1-azabicyclo[2.2.1]heptan-3-amine;

(endo,endo)-2-(Diphenylmethyl)-N-[(5-fluoro-2-methoxyphenyl)methyl]-1-azabicyclo[2.2.1]heptan-3-amine;

(endo,endo)-2-(diphenylmethyl)-N-[2-pyridylmethyl]-1-azabicyclo[2.2.1]heptan-3-amine;

(endo,endo)-2-(diphenylmethyl)-N-[(2-methylthiophenyl)methyl]-1-azabicyclo[2.2.1]heptan-3-amine;

and pharmaceutically acceptable salts and solvates thereof.

The compounds of formula (I) are antagonists of tachykinins, includingsubstance P and other neurokinins both in vitro and in vivo and are thusof use in the treatment of conditions mediated by tachykinins, includingsubstance P and other neurokinins.

In particular the compounds of formula (I) possess NK₁ -receptorantagonist activity as determined in vitro by their ability to displace³ H-substance P in the rabbit cortex using the method of Dam, V. andQuirion, R., Peptides, 7, 855-864, (1986) by using rabbit cerebralcortex membranes, and from functional studies in the rabbit thoracicaorta using the method of Brown, J. R. et al, Tachykinin Antagonists,Hakanson, R. and Sundler, F. (Eds.) Elsevier:Amsterdam, (1985)pp.305-312.

The compounds of formula (I) have been shown to exhibit substance Pantagonist activity in vivo by for example their ability to antagonisesubstance P methylester-induced bronchoconstriction in the anaesthetisedguinea-pig using the method of Hagan et al in Neuropeptides, 19,127-135, (1991) with the antagonists administered intravenously.

The compounds of formula (I) have been shown to have analgesic activityas indicated by for example their ability to inhibit acetic acid-inducedabdominal constriction in mice using the method of Collier et al inBrit. J.Pharmac. Chemother., 32, 295-310, (1968).

Also the compounds of formula (I) have been shown to haveantiinflammatory activity as indicated by for example their ability toinhibit paw oedema induced by intra-plantar administration of acombination of the NK₁ receptor agonist GR73632 and the vasodilatorneuropeptide CGRP using the method as described by Beresford, I. J. M.et al in Brit.J.Pharmacol., 102, 360, (1991).

Compounds of formula (I) have been shown to have antipsychotic activityas demonstrated by their ability to antagonise locomotor hyperactivityin mice induced by intra-cerebroventricular injection of the NK₁receptor agonist GR73632 according to the method of Elliott, P. J. etal, Brit.J.Pharmacol., 102, 73, (1991).

The compounds of formula (I) have been shown to have antiemetic activityas indicated by for example their ability to inhibit cisplatin-inducedemesis in the ferret using the test method as described hereinbefore.

Compounds of formula (I) are therefore useful as analgesics inparticular they are useful in the treatment of traumatic pain such aspostoperative pain; menstrual pain; headaches such as migraine andcluster headache; and gastrointestinal pain.

Compounds of formula (I) are also useful as antiinflammatory agents inparticular they are useful in the treatment of inflammation in asthma,influenza, chronic bronchitis and rheumatoid arthritis; in the treatmentof inflammatory diseases of the gastrointestinal tract such as Crohn'sdisease, ulcerative colitis, inflammatory bowel disease andnon-steroidal anti-inflammatory drug induced damage; inflammatorydiseases of the skin such as herpes and eczema; inflammatory diseases ofthe bladder such as cystitis and urge incontinence; and eye and dentalinflammation.

Compounds of formula (I) are also useful in the treatment of allergicdisorders in particular allergic disorders of the skin such asurticaria, and allergic disorders of the airways such as rhinitis.

Compounds of formula (I) may also be useful in the treatment of CNSdisorders in particular psychoses such as schizophrenia, mania, dementiaor other cognitive disorders e.g. Alzheimer's disease; anxiety; AIDSrelated dementia; diabetic neuropathy; multiple sclerosis; depression;Parkinson's disease; and dependency on drugs or substances of abuse; andalso the compounds of formula (I) may act as myorelaxants andantispasmodics.

Compounds of formula (I) are also useful in the treatment of emesis,where emesis is as defined hereinbefore. The compounds of formula (I)are useful in the treatment of emesis however induced. For example,emesis may be induced by the emetogens discussed hereinbefore.

Compounds of formula (I) are also useful in the treatment ofgastrointestinal disorders such as irritable bowel syndrome; skindisorders such as psoriasis, pruritis and sunburn; vasospastic diseasessuch as angina, vascular headache and Reynaud's disease; cerebralischeamia such as cerebral vasospasm following subarachnoid haemorrhage;fibrosing and collagen diseases such as scleroderma and eosinophilicfascioliasis; disorders related to immune enhancement or suppressionsuch as systemic lupus erythematosus and rheumatic diseases such asfibrositis; and cough.

The invention therefore provides a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof for use in therapy,in particular in human medicine.

There is also provided as a further aspect of the invention the use of acompound of formula (I) or a pharmaceutically acceptable salt or solvatethereof in the preparation of a medicament for use in the treatment ofconditions mediated by tachykinins, including substance P and otherneurokinins.

In an alternative or further aspect there is provided a method for thetreatment of a mammal, including man, in particular in the treatment ofconditions mediated by tachykinins, including substance P and otherneurokinins, comprising administration of an effective amount ofcompound of formula (I) or a pharmaceutically acceptable salt thereof.

It will be appreciated that reference to treatment is intended toinclude prophylaxis as well as the alleviation of established symptoms.Compounds of formula (I) may be administered as the raw chemical but theactive ingredient is preferably presented as a pharmaceuticalformulation.

Accordingly, the invention also provides a pharmaceutical compositionwhich comprises at least one compound of formula (I) or apharmaceutically acceptable salt thereof and formulated foradministration by any convenient route. Such compositions are preferablyin a form adapted for use in medicine, in particular human medicine, andcan conveniently be formulated in a conventional manner using one ormore pharmaceutically acceptable carriers or excipients.

Thus compounds of formula (I) may be formulated for oral, buccal,parenteral, topical (including ophthalmic and nasal), depot or rectaladministration or in a form suitable for administration by inhalation orinsufflation (either through the mouth or nose). Suitable pharmaceuticalcompositions are as described hereinbefore.

A proposed dose of the compounds of formula (I) is 0.1 mg/kg to about400 mg/kg bodyweight per day. It will be appreciated that it may benecessary to make routine variations to the dosage, depending on the ageand condition of the patient and the precise dosage will be ultimatelyat the discretion of the attendant physician or veterinarian. The dosagewill also depend on the route of administration and the particularcompound selected.

The compounds of formula (I) may, if desired, be administered with oneor more therapeutic agents and formulated for administration by anyconvenient route in a conventional manner. Appropriate doses will bereadily appreciated by those skilled in the art. For example, thecompounds of formula (I) may be administered in combination with asystematic anti-inflammatory corticosteroid such as methyl prednisoloneor dexamethasone, or a 5HT₃ antagonist such as ondansetron, granisetronor metoclopramide.

Compounds of formula (I), and salts and solvates thereof, may beprepared by the general methods outlined hereinafter. In the followingdescription, the groups R¹ to R³ are as previously defined for compoundsof formula (I) unless otherwise stated.

According to a first general process (A), a compound of formula (I) maybe prepared by reacting a compound of formula (II): ##STR26## with asubstituted methylamine of formula (III)

    NH.sub.2 CH.sub.2 --R                                      (III)

to form the intermediate imine, which may be isolated if required,followed by reduction of the imine using a suitable metal reducing agentsuch as a metal hydride, for example a borane hydride, alane hydride ora metal hydride complex like lithium aluminum hydride or sodiumborohydride, or an organo-metallic complex such as boranemethylsulphide, 9-borobicyclononane (9-BBN), triethylsilane, sodiumtriacetoxyborohydride, sodium cyanoborohydride and the like.Alternatively, catalytic hydrogenation may be used, for example using aplatinium catalyst in a suitable solvent e.g. ethanol.

The condensation reaction conveniently takes place in a suitable solventsuch as an alcohol (e.g. methanol), an aromatic hydrocarbon (e.g.benzene, toluene or xylene) or a chlorinated hydrocarbon (e.g.dichloromethane or dichloroethane) at a temperature ranging from ambientto the reflux temperature of the reaction mixture. The reactionpreferably takes place in the presence of a catalytic amount of asuitable acidic condensing agent such as p-toluenesulphonic acid and/ora dehydrating agent such as molecular sieves.

The reduction step conveniently takes place in a suitable solvent suchas acetonitrile, dimethylformamide, benzene, ethers such as diethylether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane and alcoholssuch as ethanol at a temperature ranging from 0° C. to the refluxtemperature of the reaction mixture.

Process (A) may also take place in one step without formation of theintermediate imine if the condensation reaction takes place in thepresence of sodium cyanoborohydride. Further reduction is thereforeunnecessary in this case.

According to a further general process (B), a compound of formula (I)may be prepared by reacting a compound of formula (IV) ##STR27## with acompound of formula (V)

    OHC--R                                                     (V)

to form the intermediate imine, which may be isolated if required,followed by reduction. The condensation and reduction steps take placeunder the conditions as described above for process (A).

Process (B) may also take place in one step as described for process(A).

Compounds of formula (II) may be prepared by reacting the compound offormula (VI) ##STR28## with phenylmagnesium bromide in a Grignardreaction. The reaction conveniently takes place in, a suitable solventsuch as an ether (e.g. tetrahydrofuran) at a temperature in the range of-10° to 25° C. and optionally in the presence of an agent which promotes1,4 addition such as a source of Cu(I) ions e.g. copper thiophenolate.

The compounds of formula (VI) may be prepared by reacting the compoundsof formula (VII) ##STR29## with benzaldehyde under suitable condensationconditions. For example the reaction conveniently takes place in thepresence of a suitable solvent such as an alcohol (e.g. ethanol) in thepresence of a base such as sodium hydroxide and at an elevatedtemperature e.g. the reflux temperature of the reaction mixture.

The ketone of formula (VII) is known (L J Street et al., J.Med.Chem.,1990, 33, 2690).

The amines of formula (IV) may be prepared by reductive amination of theketone of formula (II) with ammonium acetate in the presence of sodiumcyanoborohydride. Alternatively the ketones of formula (II) may bereacted with a suitable oximating agent such as hydroxylaminehydrochloride to give the corresponding oxime which is in turn reducedto the amine of formula (IV) using a suitable reducing agent e.g.lithium aluminum hydride or by catalytic hydrogenation for examplepalladium as catalyst.

The amines of formula (IV) may also be prepared from the N-benzylanalogues of formula (VIII) ##STR30## (where Ar represents an optionallysubstituted phenyl ring such as p-methoxyphenyl) by removing the benzylsubstituent, for example, when Ar represents p-methoxyphenyl, the benzylsubstituent may be removed using hydrobromic acid or, when Ar isunsubstituted, the benzyl group may be removed by catalytichydrogenation for example using palladium as catalyst.

Compounds of formula (VIII) may be prepared by reacting the ketone offormula (II) with NH₂ --CH₂ Ar (where Ar is defined as above) under theconditions described for process (A) above.

The intermediates of formulae (II), (IV), (VI) and (VIII) are novelcompounds and thus form a further feature of the invention.

Where it is desired to isolate a compound formula (I) as a salt, forexample a pharmaceutically acceptable salt, this may be achieved byreacting the compound of formula (I) in the form of the free base withan appropriate amount of suitable acid and in a suitable solvent such asan alcohol (e.g. ethanol or methanol), an ester (e.g. ethyl acetate) oran ether (e.g. tetrahydrofuran).

Pharmaceutically acceptable salts may also be prepared from other salts,including other pharmaceutically acceptable salts, of the compound offormula (I) using conventional methods.

The compounds of formula (I) may readily be isolated in association withsolvent molecules by crystallisation from or evaporation of anappropriate solvent to give the corresponding solvates.

When a specific enantiomer of a compound of general formula (I) isrequired, this may be obtained for example by resolution of acorresponding enantiomeric mixture of a compound of formula (I) usingconventional methods.

Thus, in one example an appropriate optically active acid may be used toform salts with the enantiomeric mixture of a compound of generalformula (I). The resulting mixture of isomeric salts may be separatedfor example by fractional crystallisation, into the diastereoisomericsalts from which the required enantiomer of a compound of generalformula (I) may be isolated by conversion into the required free base.

Alternatively, enantiomers of a compound of general formula (I) may besynthesised from the appropriate optically active intermediates usingany of the general processes described herein.

Specific diastereoisomers of a compound of general formula (I) may beobtained by conventional methods for example, by synthesis from anappropriate asymmetric starting material using any of the processesdescribed herein, or by conversion of a mixture of isomers of a compoundof general formula (I) into appropriate diastereoisomeric derivativese.g. salts which can then be separated by conventional means e.g. bychromatography or by fractional crystallisation. Alternatively, thediastereosiomers may be separable without the need for furtherderivatization.

Standard resolving methods are described for example in `Stereochemistryof Carbon compounds` by E. L. Eliel (McGraw Hill, 1962) and `Tables ofResolving Agents` by S. H. Wilen.

The various general methods described above may be useful for theintroduction of the desired groups at any stage in the stepwiseformation of the required compound, and it will be appreciated thatthese general methods can be combined in different ways in suchmulti-stage processes. The sequence of the reactions in multi-stageprocesses should of course be chosen so that the reaction conditionsused do not affect groups in the molecule which are desired in the finalproduct.

The invention is further illustrated by the following Intermediates andExamples which are not intended as a limitation of the invention. Alltemperatures are in °C. Thin layer chromatography (t.l.c.) was carriedout on silica, flash column chromatography (FCC) on silica (Merck 9385),and short path chromatography (SPC) on silica (Merck 7729). Thefollowing abbreviations are used: ether diethyl ether; System A--ethylacetate/methanol/ammonia; System B--petroleum ether/ethylacetate/methanol/ammonia.

Intermediate 1 2-(Phenylmethylene)-1-azabicyclo[2.2.1]heptan-3-one

A mixture of 1-azabicyclo[2.2.1]heptan-3-one (2.65g), benzaldehyde (3.64ml) and sodium hydroxide (1.15 g) in ethanol (25 ml) was heated atreflux for 40 min. After cooling the solvent was removed in vacuo andthe residue partitioned between dichloromethane (300 ml) and water (300ml). The aqueous layer was further extracted with dichloromethane (2×300ml). The organic extracts were combined, backwashed with brine (100 ml),dried and concentrated in vacuo to give an orange oil (5.84 g). The oilwas purified by FCC, using gradient elution with petrol/ethyl acetate6:1 to 3:1 to give the title compound as a yellow solid (3.80 g). m.p.61°-63°. TLC (petrol/ethyl acetate, 3:1) Rf 0.39.

Intermediate 2(endo)-2-(Diphenylmethyl)-1-azabicyclo[2.2.1]heptan-3-one(I) and(exo)-2-(Diphenylmethyl)-1-azabicyclo[2.2.1]heptan-3-one (II)

Phenyl magnesium bromide (1M solution in tetrahydrofuran, 37.84 ml) wasadded dropwise to an ice-bath cooled suspension of copper thiophenoxide(657 mg) in dry tetrahydrofuran (50 ml). The mixture was allowed to stirfor 10 min then a solution of 2-(phenylmethylene)-1-azabicyclo[2.2.1]heptan-3-one (3.77 g) in dry tetrahydrofuran (50 ml) was addedportionwise to the reaction mixture, which was allowed to warm to roomtemperature over 2 h. Saturated ammonium chloride (50 ml) was addedslowly to the reaction which was then allowed to stir for 20 minutes.Saturated ammonium chloride (50 ml) and ether (150 ml) were added andthe ether layer separated. The aqueous layer was further extracted withether (2×150 ml) and the combined organic extracts were backwashed withbrine (2×50 ml), dried and concentrated in vacuo to give an orange oil(7.36 g). The oil was purified by FCC, eluting with System B(30:70:0.5:0.1) to System A (100:0.5:0.1) to give isomer I as a whitesolid (2.38 g), and isomer II as a pale yellow solid (752 mg). TLC(System A, 100:2:0.1) Rf 0.30 isomer I Rf 0.61 isomer II

EXAMPLE 1(exo,ex)-2-(Diphenylmethyl)-N-[(2-methoxyphenyl)methyl]-1-azabicyclo[2.2.1]heptan-3-amine

To a solution of (exo-2-(diphenylmethyl-1-azabicyclo[2.2.1]heptan-3-one(50 mg) in dry toluene (15 ml) was added 2-methoxybenzylamine (0.035 ml)and para-toluenesulphonic acid (10 mg). The mixture was heated at refluxin a Dean-Stark water separator for 22 h. The solvent was removed invacuo and the residue dissolved in dry tetrahydrofuran (15 ml). Asolution of 9-borabicyclononane in tetrahydrofuran (0.5M, 0.72 ml ) wasadded and the reaction mixture was allowed to stir under nitrogen for 5h. A further amount of the 9-borabicyclononane solution (0.72 ml ) wasadded and stirring was continued for 20 h. 2N Sodium hydroxide (10 ml)was added to the reaction mixture and after stirring for 40 min theorganic solvent was removed in vacuo, and the residue was extracted withethyl acetate (3×25 ml). The combined organic extracts were backwashedwith brine (10 ml), dried and concentrated in vacuo to a yellow oil (242mg). The oil was purified by SPC, eluting with System A (100:4:0.5) togive the title compound as a pale yellow solid (35 mg). m.p. 142°-1440°TLC (System A, 100:10:0.5) Rf 0.38

EXAMPLE 2(endo,endo)-2-(Diphenylmethyl)-N-[2-methoxyphenyl)methyl]-1-azabicyclo[2.2.1]heptan-3-aminehydrochloride

To a solution of(endo)-2-(diphenylmethyl)-1-azabicyclo[2.2.1]heptan-3-one (500 mg) indry dichloromethane (50 ml) was added 2-methoxybenzylamine (2.7 mmol)and activated 4A molecular sieves. The reaction mixture was allowed tostir at room temperature under nitrogen for 21 h. Para-toluenesulphonicacid (50 mg) was added, and stirring was continued for 4 h after whichtime ethanol (50 ml) was added to the reaction mixture, followed bysodium borohydride (341 mg). The reaction mixture was allowed to stirfor 48 h, filtered and then water (5 ml) was added to the filtrate. Theorganic solvent was removed in vacuo and water (300 ml) added to theresidue which was extracted with dichloromethane (3×200 ml). Thecombined organic extracts were washed with brine, dried and the solventremoved in vacuo to give a yellow solid (1.0 g). The solid was purifiedby SPC, eluting with System A (100:10:0.5) to give a white foam (112 mg)which was converted into the hydrochloride salt to give the titlecompound as a white solid (13.2 mg), m.p. 174°-60°. TLC (System A,100:10:0.5) Rf 0.28

EXAMPLE 3(exo,endo)-2-(Diphenylmethyl)-N-[(5-fluoro-2-methoxyphenyl)methyl]-1-azabicyclo[2.2.1]heptan-3-aminedihydrochloride

A mixture of(exo, endo)-2-(diphenylmethyl)-1-azabicyclo[2.2.1]heptan-3-one (500 mg ), 4-toluenesulphonic acid (70.0 mg) and5-fluoro-2-methoxy benzylamine (420 mg) in anhydrous toluene (20 ml) washeated under reflux with stirring in a Dean-Stark water separator for 18h. Upon cooling to room temperature, the solvent was evaporated in vacuoand the residue was dissolved in anhydrous tetrahydrofuran (7 ml) andcooled to 0°. A solution of 9-borabicyclononane in tetrahydrofuran (7.2ml of 0.5M) was added, and stirring was continued at room temperaturefor 48 h. The solvent was evaporated in vacuo and the residue wasdiluted with 2M aqueous sodium hydroxide solution (30 ml) and extractedwith ethyl acetate (3×20 ml). The combined organic extracts were washedwith brine (1×10 ml), dried and concentrated in vacuo to leave a yellowoil. The oil was purified by column chromatography on silica (MerckHF254) eluting with a mixture of ethyl acetate and methanol (containing5% NH₃) (95:5) to give two fractions, which were treated with etheralhydrogen chloride to give the title compound (160 mg) as a white solid,m.p. 162°-164°.

TLC (5% methanol/ammonia:ethyl acetate, 5:95) Rf 0.2(5) and also

EXAMPLE 4(exo,exo)-2-(Diphenylmethyl)-N-[(5-fluoro-2-methoxyphenyl)methyl]-1-azabicyclo[2.2.1]heptan-3-aminedihydrochloride

(100 mg) as a white solid, m.p. 168°-170°. TLC (5%methanol/ammonia:ethyl acetate, 5:95) Rf 0.2(0)

EXAMPLE 5(endo,endo)-2-(Diphenylmethyl)-N-[2-pyridylmethyl]-1-azabicyclo[2.2.1]heptan-3-aminehydrochloride

To a solution of(endo)-2-(diphenylmethyl)-1-azabicyclo[2.2.1]heptan-3-one (250 mg) and2-aminomethylpyridine (102 μl) in dichloroethane (20 ml ) was addedsodium triacetoxyborohydride (286 mg), followed by acetic acid (57 μl),and the reaction stirred for 48 h. The reaction mixture was diluted withdichloromethane (30 ml) and washed successively with saturated sodiumbicarbonate solution (2×50 ml), water (50 ml) and brine (50 ml). Theorganic solution was dried, and evaporated to a gum. FCC, eluting withSystem A (75:25:1) gave a gum (170 mg) which was converted to thehydrochloride salt with methanolic hydrochloric acid to give the titlecompound (196 mg) as a white solid. m.p. 170°-172° (decomp) T.l.c.(System A 75:25:1) Rf 0.34.

EXAMPLE 6(endo,endo)-2-(Diphenylmethyl)-N-[(2-methylthiophenyl)methyl]-1-azabicyclo[2.2.1]heptan-3-aminehydrochloride

A mixture of (endo)-2-(diphenylmethyl)-1-azabicyclo[2.2.1]heptan-3-one(100 mg), 2-methylthiobenzylamine (83 mg), paratoluenesulphonic acid(205 mg) acid 4A molecular sieves (2 g) were stirred in methanol (10mls) for 3 h. Sodium cyanoborohydride (113 mg) was added, and thereaction mixture was stirred for 48 h. The mixture was filtered, and thefiltrate concentrated to dryness. The residue was partitioned betweenethyl acetate (50 ml) and saturated sodium bicarbonate solution (50 ml),the organic layer washed with water (2×50 ml) and brine (50 ml), dried,and concentrated in vacuo to give a yellow oil. FCC eluting with SystemA (100:10:0.5) gave a gum (39 mg) which was converted to thehydrochloride salt with methanolic hydrochloric acid to give the titlecompound (44 mg) as a pale yellow solid. m.p. 168°-70° (decomp) T.l.c.(System A: 100:10:1) Rf 0.58

Biological Data

The anti-emetic activity of the test compound (±)cis-3-(2-methoxybenzylamino)-2-phenyl piperidine was demonstrated by itsability to inhibit cisplatin-induced emesis in the ferrett.

In this model of emesis the onset of retching and vomiting occursapproximately 1 hour after the administration of cisplatin (200 mg/m²i.p.). At the first retch in response to cisplatin, the test compoundwas administered (e.g. i.p., p.o., i.v., s.c., i.c.v.) and its effect onemesis determined by comparison with appropriate controls (e.g. water).

The test compound exhibited anti-emetic activity when administered at adose of 3 mg/kg i.p.

The above test compound (3 mg/kg i.p) also exhibited anti-emeticactivity following simultaneous administration with the emetogenscyclophosphamide (200 mg/kg i.p), morphine (0.5 mg/kg s.c), ipecacuanha(2 mg/kg p.o) and copper sulphate (40 mg/kg i.p.).

The (2S,3S) enantiomer of the test compoundcis-3-(2-methoxybenzylamino)-2-phenyl piperidine inhibitedcisplatin-induced emesis in the ferrett when administered at a dose of 3mg/kg i.p. The (2R,3R) enantiomer of the above test compound, which is1000-fold less active as an NK₁ receptor antagonist than the (2S,3S)enantiomer, was inactive in the above emesis test.

The compound of formula (I)(exo,exo)-2-(diphenylmethyl)-N-[(2-methoxyphenyl)methyl]-1-azabicyclo[2.2.1]heptan-3-amine(Example 1) also inhibited cisplatin-induced emesis in the ferrett whenadministered at a dose of 5 mg/kg i.p.

We claim:
 1. A method for the treatment of a mammal, suffering from orsusceptible to emesis, comprising administration of an effective amountof a tachykinin antagonist which is an NK, receptor antagonist.
 2. Amethod according to claim 1 wherein said emesis is induced by cancerchemotherapeutic agents, radiation sickness, radiation therapy, poisons,toxins, pregnancy, vestibular disorders, post-operative sickness,gastrointestinal obstruction, reduced gastrointestinal motility,visceral pain, migraine, increased intercranial pressure, decreasedintercranial pressure, or opioid analgesics.
 3. A method according toclaim 2 wherein said emesis is induced by a cancer chemotherapeuticagent.
 4. A method according to claim 3 wherein said cancerchemotherapeutic agent is selected from cyclophosphamide, carmustine,lomustine, chloroambucil, dactinomycin, doxorubicin, mitomycin-C,bleomycin, cytarabine, methotrexate, 5-fluorouracil, etoposide,vinblastine, vincristine, cisplatin, dacarbazine, procarbazine,hydroxyurea, and combinations thereof.
 5. A method according to claim 4wherein said emesis is induced by cisplatin.
 6. A method according toclaim 4 wherein said emesis is induced by cyclophosphamide.
 7. A methodaccording to claim 1 wherein said emesis is induced by morphine,ipecacuanha or copper sulphate.
 8. A method according to claim 1 whereinthe NK₁ antagonist is a compound of formula: ##STR31## wherein Ar isthienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl;R is hydrogenor alkyl having from one to four carbon atoms; R¹ is cycloalkyl havingfrom five to seven carbon atoms, norbornyl, pyrrolyl,2,3-dihydrobenzofuranyl, thienyl, alkoxythienyl having from one to threecarbon atoms in the alkoxy moiety, pyridyl, hydroxypyridyl, quinolinyl,indolyl, naphthyl, alkoxynaphthyl having from one to three carbon atomsin the alkoxy moiety, biphenyl 2,3-methylenedioxyphenyl, or phenyloptionally substituted with up to two substituents selected from cyano,nitro, amino, N-monoalkylamino having from one to three carbon atoms inthe alkyl moiety, fluorine, chlorine, bromine, trifluoromethyl, alkylhaving from one to three carbons, alkoxy having from one to three carbonatoms, allyloxy, hydroxy, carboxy, alkoxycarbonylbenzyloxy having fromone to three carbon atoms in the alkoxy moiety, carboxamido orN,N-dialkylcarboxamido having from one to three carbon atoms in thealkyl moiety; and R¹¹ is branched chain alkyl having from three to fourcarbon atoms, branched chain alkenyl having from five to six carbonatoms, cycloalkyl having from five to seven carbon atoms, furyl,thienyl, pyridyl, indolyl, biphenyl, or phenyl optionlly substitutedwith up to two substituents selected from fluorine, chlorine, bromine,trifluoromethyl, alkyl having from one to three carbon atoms, alkoxyhaving from one to three carbon atoms, carboxy, alkoxycarbonyl havingfrom one to three carbon atoms in the alkoxy moiety orbenzyloxycarbonyl, with the proviso that said R¹¹ is always other thanunsubstituted phenyl, fluorophenyl, chlorophenyl, bromophenyl oralkylphenyl when said R¹ is unsubstituted phenyl, pyrrolyl or thienyland Ar is other than thienyl; ##STR32## wherein R¹ is hydrogen or (C₁-C₆)alkyl; R² is phenyl, pyridyl, thienyl or furyl, and R² mayoptionally be substituted with from one to three substituentsindependently selected from (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, chloro,fluoro, bromo, iodo and trifluoromethyl; R³ is phenyl, naphthyl,pyridyl, thienyl or furyl, and R³ may optionally be substituted with oneto three substituents independently selected from (C₁ -C₄)alkyl, (C₁-C₄)alkoxy, chloro, fluoro, bromo, iodo and trifluoromethyl; ##STR33##wherein Y is (CH₂)_(m) wherein m is an integer from one to three, or Yis a group of the formula ##STR34## P is an integer from zero to one; Zis oxygen, sulfur, amino, N-(C₁ -C₃)alkylamino or --(CH₂)_(n) -- and nis zero, one or two; R¹ is cycloalkyl having from five to seven carbonatoms, pyrrolyl, thienyl, pyridyl, phenyl or substituted phenyl, whereinsaid substituted phenyl is substituted with one to three substituentsselected from fluorine, chlorine, bromine, trifluoromethyl, alkyl havingfrom one to three carbon atoms, alkoxy having from one to three carbonatoms, carboxy, alkoxycarbonyl having from one to three carbons in thealkoxy moiety and benzyloxycarbonyl; and R² is furyl, thienyl, pyridyl,indolyl, biphenyl, phenyl or substituted phenyl, wherein saidsubstituted phenyl is substituted with one or two substituents selectedfrom fluroine, chlorine, bromine, trifluoromethyl, alkyl having from oneto three carbon atoms, alkoxy having from one to three carbon atoms,carboxy, alkoxycarbonyl having from one to three carbon atoms the alkoxymoiety and benzyloxycarbonyl;or a pharmaceutically acceptable saltthereof.